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Biomedical subjects

P J Rice

Publications and source records attributed to P J Rice.

At least 19 recordsLinked to original sources
PubMed1995

Diastolic dysfunction is not related to changes in glycaemic control over 6 months in type 2 (non-insulin-dependent) diabetes mellitus. A cross-sectional study.

Diastolic dysfunction may be the earliest marker of a diabetes-induced heart muscle disease which leads to the progressive development of cardiac failure. Left ventricular diastolic function was indirectly assessed using pulsed wave Doppler ultrasound mitral-flow velocities in 20 normotensive patients with a new diagnosis of type 2 diabetes mellitus, normal cardiac function and no evidence of coronary artery disease and in 16 age-matched normal subjects. Peak velocities of early (E) and late (A) left ventricular filling were measured. The median (interquartile ranges) peak E/A ratio was significantly reduced in the diabetic group 0.96 (0.8-1.2) vs 1.2 (1.1-1.3), P < 0.01. Despite improvements in glycaemic control over 3 months, HbA1c 9.9% (7.6%-10.5%) to 7.4% (6.5%-7.9%), P < 0.001, maintained at 6 months, HbA1c 7.0% (6.4%-7.3%), there were no changes in the E/A ratio, 0.96 (0.83-1.15) and 0.95 (0.83-1.17), respectively. Furthermore, there was no correlation between percentage change in HbA1c and E/A ratio over 6 months. The results of this study suggest that in patients with type 2 diabetes mellitus and normal systolic function, diastolic function was impaired at diagnosis and was not affected by an improvement in the glycaemic control.

Blood Glucose↗
PubMed1992

The anatomical distribution of plasma fibrinolytic activity in man during cardiac catheterisation.

Regional circulating plasma levels of fibrinolytic activity were assessed in 15 patients undergoing cardiac catheterisation. The euglobulin clot lysis time (ECLT) was longer in the abdominal aorta (AA) than the inferior vena cava (IVC), (median difference -17.5 min, p = 0.008). This was associated with higher inhibition of plasminogen activator activity (PAI) in the AA than IVC, -1.75 IU/ml, p = 0.002. In the venous circulation the ECLT was higher in the peripheral venous sample than in the IVC, -25.5 min, p = 0.003, with higher PAI peripherally than in the IVC, -1.9 IU/ml, p = 0.001. There were no differences in ECLT, PAI, PAI-1:Ag or t-PA:Ag throughout the arterial circulation. These results demonstrate higher fibrinolytic activity with lower inhibitor activity in the venous compared to the arterial circulation. Within the venous circulation fibrinolytic activity is lower peripherally with increased inhibitor activity.

Aged↗
PubMed1992

Protein kinase C-mediated contractile response of the rat vas deferens.

The role of protein kinase C (PKC) in mediating contractile responses in the rat vas deferens was studied. Phorbol-12,13-diacetate (PDA) in the presence of 20 mM K+ elicited a concentration-dependent response with an EC50 of 190 nM. The non-PKC activator 4 alpha-phorbol (2 microM) was unable to elicit contraction in 20 mM K+ buffer. Incubation of rat vas deferens with the PKC inhibitor iso-H7 (30 microM) attenuated the response to norepinephrine (NE) and neurokinin A, with maximal effects depressed to 42 and 39% of control, respectively. Responses to 60 mM K+ and 2 microM PDA (20 mM K+) was also significantly inhibited by iso-H7. In the presence of 2 microM PDA and 20 mM K+, the NE concentration-effect curve was shifted 3.6-fold to the right of the control curve in a parallel manner. 4 alpha-Phorbol (20 mM K+) at the same concentration did not produce this effect. These results suggest a significant role for PKC in the contractile response of the rat vas deferens.

Analysis of Variance↗
PubMed1992

Pharmacokinetics of nadolol in children with supraventricular tachycardia.

The pharmacokinetics of intravenous and oral nadolol, a long-acting beta-adrenoceptor blocking agent, were investigated in six children receiving the drug for treatment of supraventricular tachycardia. In the youngest patient (age 3 months), no distribution phase was seen. In children younger than 22 months of age, nadolol is more rapidly eliminated (t1/2 = 4.3 hours or less) than in older children, in whom elimination is more similar to that in adults (t1/2 approximately 7.3-15.7 hours). After intravenous administration, nadolol displayed two-compartment pharmacokinetics with a distribution phase (t1/2 = 0.2-1.1 hours) followed by elimination. Large changes in nadolol pharmacokinetics may occur during the first year of life. Nadolol should be used cautiously in infants.

Adolescent↗
PubMed1992

Absence of denervation supersensitivity to neurokinin A in the rat vas deferens.

1. Unilateral denervation of the rat vas deferens (RVD) was performed under anesthesia. The animals were allowed to recover 4 or 10 days and then concentration-effect (C-E) curves to noradrenaline (NA) and neurokinin A (NKA) were constructed in denervated and control RVD. 2. Tissues denervated 4 or 10 days produced NA responses shifted 20-fold to the left with maxima 130% of control. 3. NKA C-E curves in denervated RVD were not significantly different from control. 4. Phenylephrine exhibited a 6-fold increase in tissue sensitivity after denervation. 5. Chronic denervation of the vas deferens resulted in significant postsynaptic supersensitivity to alpha 1-adrenoceptor agonists but not to NKA.

Adrenergic alpha-Agonists↗
PubMed1992

Three-dimensional electrocardiography in the rat.

Three-dimensional electrocardiography with computerized analysis provides a means to rapidly collect and quantitatively analyze electrocardiographic data from rats. Electrical activity at each point in time can be expressed quantitatively as a vector with magnitude and direction. Rats are fitted with plate and needle electrodes in three mutually perpendicular axes: X (right to left), Y (rostral to caudal), and Z (ventral to dorsal). Electrocardiographic signals are recorded on paper and also collected at 1000/sec using an IBM-compatible computer equipped with a fast A/D convertor. Signals are analyzed using an interactive program written in Turbo PASCAL which transforms data into an array consisting of vector magnitude and direction at each time point. The data are further used to produce both a tabular report and graphic output. This method retains simplicity while extending the accuracy of electrocardiographic (ECG) measurement. It literally adds another dimension of information to the three-lead ECG most commonly measured in rats.

Animals↗
PubMed1992

The effect of exercise and heart rate on fibrinolytic activity.

The effect of heart rate on plasma fibrinolytic activity was investigated in nine patients with dual chamber cardiac pacemakers before and after 10 min of stimulated tachycardia to 123 beats/min. The results were compared to seven volunteers who performed submaximal exercise to 90% target heart rate and to five of the seven who underwent a second period of exercise to a heart rate of 120 beats/min. During submaximal exercise (mean heart rate 152 beats/min) the median ECLT fell from 248 min (interquartile range 147.5-305) to 90 (55-202) P less than 0.01 and t-PA:Ag increased from 6.1 ng/ml (3.92-7.95) to 9.3 (8.45-12.7), P less than 0.025. PAI and PAI-1:Ag fell from 12.0 IU/ml (5.85-15.5) to 4.1 (1.85-11.67), P less than 0.01, and 9.7 ng/ml (2.8-10.6) to 6.7 (2.1-9.9), P less than 0.01 respectively. A lower level of exercise to 120 beats/min resulted in a reduction in ECLT from 215 min (167.5-228.5) to 135 (116-154), P = 0.05 and an increase in t-PA:Ag from 4 ng/ml (3.07-4.45) to 5.0 (3.3-5.22) P less than 0.05. PAI and PAI-1:Ag fell from 7.6 IU/ml (3.27-8.5) to 7.1 (2.77-7.4) and from 7.7 ng/ml (6.0-7.92) to 6.4 (4.8-7.3) respectively but these changes were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Imidazoline desensitization of epinephrine responses in rat vas deferens.

Repeated exposure of the rat vas deferens to the imidazoline oxymetazoline (OXY) results in a progressive loss of response which can appear selective for imidazoline agonists. The present study tests the hypothesis that imidazolines produce desensitization through prolonged blockade or inactivation of alpha-1 adrenoreceptors. Repeated exposure to OXY, naphazoline (NPZ) or tetrahydrozoline (THZ) produces a concentration- and time-dependent rightward shift and depression of the (-)-epinephrine concentration-effect curve, suggesting a mechanism of prolonged receptor blockade or inactivation. (-)-Epinephrine Kd values were similar when estimated after either receptor inactivation with phenoxybenzamine or repeated exposure to imidazolines. The differences in the ability of individual imidazolines to produce desensitization (order of potency: OXY greater than NPZ greater than or equal to THZ) do not follow their intrinsic activity (NPZ approximately THZ approximately OXY) or affinity (OXY greater than or equal to NPZ greater than THZ). The ability of individual imidazoline and phenethylamine agonists to produce a response in imidazoline-desensitized rat vas deferens reflects agonist intrinsic efficacy. Desensitization by imidazoline exposure does not affect contraction produced by either KCl or neurokinin A. Imidazolines produce effects similar to receptor inactivation and their desensitization in vas deferens can be explained without invoking an imidazoline subtype of alpha-1 adrenoreceptor.

Adrenergic alpha-Antagonists↗
PubMed1989

Pharmacologic implications of alpha-adrenoreceptor interactive parameters for epinephrine enantiomers in the rat vas deferens.

After alkylation of a fraction of the total alpha-adrenoreceptors by phenoxybenzamine in rat vas deferens, the dissociation constants of (-)- and (+)-epinephrine in functional studies were 7 X 10(-7) M and 2 X 10(-5) M, respectively. In the adrenoreceptor-containing tissue fraction, when 3H-labeled WB4101 was used as the interacting ligand, for each enantiomer two affinity sites were found. Only the low-affinity dissociation constant for each isomer correlates with the constant obtained from the functional studies. If the change in Gibb's free energy, delta G degrees, is calculated from the low-affinity binding constants, the values -8.1 and -6.2 kcal/mol for (-)- and (+)-isomer, respectively, are obtained. The small difference in the value between isomers is consistent with the view that the benzylic hydroxyl group of the (-)-isomer forms a hydrogen bond with the receptor. The interaction of epinephrine with this receptor appears to be driven largely by the entropy of the drug-receptor interaction with only a small nonstereoselective contribution from the enthalpy of interaction.

Animals↗
PubMed1989

Epinephrine enantiomers: affinity, efficacy and potency relationships in rat smooth muscle tissues.

The purpose of this study was to examine the relationship between affinity and efficacy for the epinephrine enantiomers in rat tissues. Potency and was measured for (-)- and (+)-epinephrine in aorta, longitudinal muscle of portal vein, spleen and vas deferens. After partial alpha-adrenoreceptor inactivation with phenoxybenzamine, dissociation constant was estimated for each enantiomer and used to estimate efficacy. Whereas potency, affinity and efficacy vary between tissues, there is a constant relationship between (-)- and (+)-enantiomer; the enantiomeric ratio is constant for both potency and affinity. Efficacy is similar for the enantiomers in each tissue. The potency difference between epinephrine enantiomers at alpha-adrenoreceptors in rat tissues is due to differences in affinity rather than efficacy.

Animals↗
PubMed1988

Sensitivity of caudal arteries and the mesenteric vascular bed to norepinephrine in DOCA-salt hypertension.

This study was undertaken to determine what factors might contribute to arterial supersensitivity to norepinephrine associated with deoxycorticosterone acetate (DOCA)-salt hypertension in the rat. Experimental groups of male rats were uninephrectomized and 1 week later began receiving twice weekly injections of DOCA (20 mg/kg s.c. in sesame oil) plus 1% NaCl and 0.2% KCl in their drinking water. For each experimental group, a group of age-matched male rats underwent a sham operation and received injections of sesame oil and the NaCl-KCl drinking water. Perfused caudal arteries from 3-week-hypertensive rats were supersensitive to intraluminal and extraluminal norepinephrine administration. However, this difference in sensitivity between hypertensive and control caudal arteries was demonstrable at low rates of perfusion, 0.5 to 1.0 ml/min, but not at rates of 2.0 to 2.6 ml/min. The supersensitivity was not due to differences in neuronal uptake or to inhibition of extraneuronal uptake by DOCA. The perfused mesenteric vascular bed from 3- or 6-week-hypertensive rats was also supersensitive to intraluminal norepinephrine. However, the demonstration of supersensitivity in the mesenteric vasculature was independent of perfusion rate (2.3-6.8 ml/min) and perfusion pressure in the range of 30 to 60 mm Hg. There was little or no supersensitivity to transmural nerve stimulation in either the caudal artery or the mesenteric vasculature, a finding consistent with the observed decrease in endogenous norepinephrine content. Microelectrodes were used to determine resting membrane potential in the smooth muscle cells. No differences in resting membrane potential were detected between caudal or mesenteric arteries from hypertensive compared with control rats 2, 3, or 6 weeks after initiation of the DOCA-salt regimen. It is concluded that 1) the perfusion rate is a critical factor in designing experiments to test the sensitivity of caudal arteries to drugs, 2) the perfused mesenteric vascular bed is a useful preparation for studying sensitivity of blood vessels in hypertension, 3) the supersensitivity of blood vessels in the DOCA-salt model may be of greater importance relative to circulating catecholamines than to sympathetic innervation, and 4) the supersensitivity of blood vessels to norepinephrine in the DOCA-salt model is not due to changes in neuronal uptake, extraneuronal uptake, or membrane potential of the vascular smooth muscle cells.

Animals↗
PubMed1987

Asymmetric catecholimidazolines and catecholamidines: affinity and efficacy relationships at the alpha adrenoreceptor in rat aorta.

The epinephrine (EPI) stereoisomers interact with the alpha adrenoreceptor according to the Easson-Stedman model with an order of potency of (-)-EPI greater than (+)-EPI = Epinine. A series of catecholimidazolines (CI) and catecholamidines (CA) were compared with the EPI series for the relationship of stereoisomerism to potency, affinity and efficacy. Within each group of desoxy compound and stereoisomers obtained by -OH substitution at the benzylic position, differences in potency were found to be due solely to differences in affinity; differences in efficacy were not significant. The stereoisomers of the CI and CA series followed the order of potency predicted by the Easson-Stedman model: (-)-isomer greater than (+)-isomer. The desoxy analogs, in contrast to the prediction based on the Easson-Stedman hypothesis, were equal (CI) or greater (CA) in potency than the more potent (-)-isomer of each series. Possible explanations for this include differences in physical properties in the desoxy analogs of CI and CA compared with the corresponding enantiomers. Methyl or benzyl substitution at C-4 of the imidazoline ring decreased potency over 100-fold; potency differences between enantiomers were negligible. Thus, the Easson-Stedman model cannot be extended to either the CI or CA series of alpha adrenoreceptor agonists.

Amidines↗
PubMed1987

Norepinephrine depletion and sensitivity changes in rat heart induced by pretreatment with reserpine.

Depletion of norepinephrine, sensitivity to isoproterenol and sensitivity to tyramine in rat atria were investigated after various doses and schedules of pretreatment of rats with reserpine. Virtually complete depletion of norepinephrine occurred in both right and left atria and ventricles after doses of 1.0 mg/kg/day of reserpine for one or more days of pretreatment. A smaller dose, 0.3 mg/kg/day, produced lesser depletion, and a larger dose, 2.5 mg/kg/day, caused severe central nervous system depression and high mortality. Chronic treatment (5 days or longer) with the 1.0-mg/kg/day dose produced supersensitivity of right atria to the chronotropic, but not inotropic, responses to isoproterenol. Chronic treatment with this dose for 7 days produced inotropic supersensitivity in left atria. Most of the schedules of pretreatment with reserpine depressed the maximum response to tyramine. However, the data indicate that the tyramine-releasable norepinephrine was not a consistent reflection of the total norepinephrine pool, even when depletion was very pronounced. The effects of depletion of cardiac stores of norepinephrine with reserpine in comparison with the effects of cardiac sympathectomy are discussed.

Animals↗
PubMed1985

Surgical sympathectomy of the heart in rodents and its effect on sensitivity to agonists.

A new procedure for sympathetic denervation of the hearts of rats and guinea pigs is described. Bilateral removal of the inferior and medial cervical ganglia results in almost complete loss of catecholamines from atria and ventricles, disappearance of catecholamine-associated histofluorescence from the region of the sinoatrial node and marked depression of the chronotropic concentration-response curve for tyramine in right atria of both species. Seven days after bilateral sympathectomy, the chronotropic concentration-response curve for isoproterenol is shifted to the left by a factor of 3.3 in the rat and 1.7 in guinea-pig right atria. The chronotropic concentration-response curve for histamine was not shifted by sympathectomy in the guinea-pig right atrium. Inasmuch as the rat atrium does not respond to histamine, similar experiments could not be done in the rat. The inotropic concentration-response curve for isoproterenol in electrically driven left atria was not affected by 7 days of sympathectomy in either species. These results indicate that chronic surgical sympathectomy of the heart can be successfully accomplished in the rat and guinea pig. Such sympathectomy induces a postjunctional supersensitivity in guinea-pig right atria which is qualitatively and quantitatively similar to that described previously for chronic treatment with reserpine. Bilateral surgical sympathectomy provides a valuable tool for future investigations of the cellular basis of supersensitivity in the myocardium.

Animals↗
PubMed1983

Differences in the applicability of the easson-stedman hypothesis to the alpha 1- and alpha 2-adrenergic effects of phenethylamines and imidazolines.

The enantiomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline and the corresponding desoxy derivative, 2-(3,4-dihydroxybenzyl)imidazoline, were evaluated at alpha 1- and alpha 2-adrenergic receptors to test the applicability of the Easson-Stedman hypothesis to the imidazoline class of alpha-adrenergic agonists. A series of closely related phenethylamines was included for comparison. The Easson-Stedman hypothesis states that optically active adrenergic agonists possessing an asymmetric hydroxyl-substituted benzylic carbon atom will have the following relative potencies: R(-) greater than S(+) = desoxy. While the phenethylamines were found to adhere to the Easson-Stedman hypothesis at both alpha 1- and alpha 2-adrenergic receptors, the optically active imidazolines did not. These findings further support our previous observations that the phenethylamines and imidazolines may interact differently with alpha-adrenergic receptors.

Animals↗
PubMed1983

Optically active catecholimidazolines: a study of steric interactions at alpha-adrenoreceptors.

The optical isomers and deoxy form of 2-(3,4, alpha-trihydroxybenzyl)imidazoline hydrochloride were examined for their alpha-adrenergic activity on rat aorta. The rank order of stimulant activity was deoxy (2) congruent to (R)-(-)-1 greater than (S)-(+)-1. This is in contrast to catecholamines in which the order of activity is (R)-(-)-epinephrine greater than (S)-(+)-epinephrine = epinine (deoxyepinephrine). The relative order of potency for the isomers of 2-(3,4, alpha-trihydroxybenzyl)imidazoline is different than that predicted by the Easson--Stedman theory for stereoisomers of catecholamines. Also, substitution of the deoxy compound 2 with substituents, methyl or benzyl, in the 4-position lowers the alpha-adrenergic agonist activity, and differences observed between optical isomers were small.

Animals↗